Celiac disease (CD) is a major public health problem affecting up to 1% of the general population and leading to significant morbidity and mortality. While the HLA-DQ genotype explains approximately 40% of familiar clustering of CD, at least eight non-HLA genes have been shown to be associated with the disease in recent GWA studies1. Such studies are performed in case control studies, and none have been investigated in a prospective cohort design. The genetic architecture of CD susceptibility of the multiethnic U.S. population and the risk associated with combinations of susceptibility and protective variants is largely unknown. We are proposing to address these issues in a unique large cohort of children followed prospectively for development of the CD phenotype (R01 DK50979, 9/1995-11/2011, M. Rewers, P.I.). Finally we will develop risk models based on numbers of CD loci expressed combined with environmental data collected in the prospective cohort to assess individuals at extreme risk for CD. RELEVANCE: Celiac disease (CD) is a major public health problem affecting up to 1% of the general population and leading to significant morbidity and mortality. The proposed population-based project will examine the predictive value of genetic variants reported by Celiac disease (CD) genome-wide association studies (GWAS) and explore potential interactions between these variants and prospectively ascertained dietary exposures, e.g., timing of gluten introduction and amount of intake, breast-feeding duration in the development of CD, as well as, develop risk models based on numbers of CD loci expressed combined with environmental data collected in the prospective cohort to assess individuals at extreme risk for CD.